Category Archives: genetics

Expanding the Historical Plague Paradigm

When the first complete genomic sequence of Yersinia pestis was published on October 4, 2001 the world was naturally focused elsewhere, on anthrax bioterrorism — the Amerithrax incident was then in its second week– and the September 11 attacks were just over three weeks old. As the world redeveloped bioterrorism assessments and plans, plague was placed on lists along with anthrax, smallpox and yes, ebola as agents of national security concern and response.  Although plague produced more annual cases than most agents on the category A bioterrorism list, it was placed on the list primarily based on its historical reputation and past attempts to weaponize it (also based on its reputation). Yet, in 2001 there was a fierce debate ranging among historians and others on whether Yersinia pestis was the agent of the Black Death at all.

It would take another ten years before genomics would revolutionize our understanding of the historical plague. On October 12, 2011 the first draft sequence of an ancient plague genome was published. Finally, adding to the detection of Yersinia pestis DNA tests previously done on remains, the draft sequence isolated from the East Smithfield Black Death cemetery in London solidified consensus that Yersinia pestis is the agent of the Black Death pandemic.  Meanwhile, the phylogenetic tree of Yersinia pestis had been constructed based on the genetic sequence of isolates from all over the globe. Ancient and modern Yersinia pestis genomes were opening a new window into the history of the species.

As fundamental as genomic analysis is to the new understanding of historical plague, it is a skeleton of data that is open to many different historical interpretations. Science can’t adequately explain the historic plague epidemics alone; it takes historical context. In the inaugural double issue of The Medieval Globe,  Pandemic Disease in the Medieval World: Rethinking the Black Death (open access) begins this process. The eleven articles in this issue take the genetic identification of Yersinia pestis  as the agent of the Black Death as foundational and integrate modern biological and epidemiological information into a new global Old World assessment of the history of the Black Death and subsequent epidemics. Each of these articles lays the groundwork for future interdisciplinary work between historians, anthropologists, biologists, epidemiologists and others.

In my own contribution to this issue, “The Black Death and the Future of the Plague” I discuss why plague is still important in the modern world and for our future. Plague has played an integral role in the development of the re-emerging infectious diseases paradigm and is an agent of biosecurity concern. I review the current state of plague around the world, what we have learned about plague epidemiology and transmission, and how it can be applied to historic epidemics. I also make my case for why the study of the entire history of plague is uniquely important and why the sciences and humanities must move forward together.  I hope we can engage in a discussion on these issues here in the comments section, on twitter or by email.

My own interest and awareness of the issues surrounding the study of the plague was transformed when I had the great fortune to be invited by Monica Green to participate in a session at the American Historical Association annual meeting in New Orleans, January 2013. The group of plague scholars gathered there has largely remained in contact and expanded our network into an informal working group that has enriched all of our scholarship.  No one can become fully conversant with all of the disciplines involved in the study of even one epidemic, much less the entire history of the plague.  Working in disciplinary seclusion will not produce a satisfying paradigm or widespread consensus. It takes work, patience and some tolerance of how other disciplines work, but I have found it to always be worth it. I hope you will agree.

Some references for the milestones mentioned:

Parkhill, J., Wren, B. W., Thomson, N. R., Titball, R. W., Holden, M. T., Prentice, M. B., et al. (2001). Genome sequence of Yersinia pestis, the causative agent of plague. Nature, 413(6855), 523–527. doi:10.1038/35097083

Morelli, G., Song, Y., Mazzoni, C. J., Eppinger, M., Roumagnac, P., Wagner, D. M., et al. (2010). Yersinia pestis genome sequencing identifies patterns of global phylogenetic diversity. Nature Genetics, 1–20. doi:10.1038/ng.705

Little, L. K. (2011). Plague Historians in Lab Coats. Past & Present, 213(1), 267–290. doi:10.1093/pastj/gtr014

Bos, K. I., Schuenemann, V. J., Golding, G. B., Burbano, H. A., Waglechner, N., Coombes, B. K., et al. (2011). A draft genome of Yersinia pestis from victims of the Black Death. Nature, 1–5. doi:10.1038/nature10549

Pandemic Disease in the Medieval World: Rethinking the Black Death. Edited by Monica Green. The Medieval Globe, 1 (1), 2014.

Autumn Reading

Autumn 2014

So much for my plan to do monthly reading updates. I think quarterly might be more feasible. It seems like the fall has flown by and was not as productive as I would have liked. Isn’t that always the way?

So I’m currently working my way through Cameron’s Anglo-Saxon Medicine and then next up will be the brand new second edition of Mitchell’s A History of the Later Roman Empire AD 284-641.

Books finished:
  • Matilda Holmes, Animals in Saxon and Scandinavian England: Backbones of Economy and Society. Sidestone press, 2014 (reviewed here)
  • Prokopius, The Secret History and Related Texts. Anthony Kaldellis, ed. Hackett, 2010.
  • David Quammen. Ebola: A Natural and Human History of a Deadly Virus. 2014. (excerpted, adapted and updated from his Spillover)
Notable Papers
  • Setzer, T. J. (2014). Malaria detection in the field of paleopathology: A meta-analysis of the state of the art. Acta Tropica, 140, 97–104. doi:10.1016/j.actatropica.2014.08.010 (summarized here)
  • Christina Lee. (2014). Invisible enemies: the role of epidemics in the shaping of historical events in the early medieval period in. Social Dimensions of Medieval Disease and Disability, 1–17.
  • Sallares, R. (2006). Role of environmental changes in the spread of malaria in Europe during the Holocene. Quaternary International, 150(1), 21–27. doi:10.1016/j.quaint.2006.01.005
  • Sallares, R., Bouwman, A., & Anderung, C. (2004). The spread of malaria to Southern Europe in antiquity: new approaches to old problems. Medical History, 48(3), 311–328.
  • Collins, W. E., & Jeffery, G. M. (2007). Plasmodium malariae: Parasite and Disease. Clinical Microbiology Reviews, 20(4), 579–592. doi:10.1128/CMR.00027-07
  • Schreg, Rainer. (2014) “Ecological Approaches in Medieval Rural Archaeology” European Journal of Archaeology, 17 (1), 83-119.
  • Flaherty, E. (2014). Assessing the distribution of social–ecological resilience and risk: Ireland as a case study of the uneven impact of famine. Ecological Complexity, 19, 35–45. doi:10.1016/j.ecocom.2014.04.002
  • SHARPE, W. D., &  Isidore of Seville. (1964). Isidore of Seville: the Medical Writings. An English Translation with an Introduction and Commentary. Transactions of the American Philosophical Society, New Series, 54(2), 1–75.
  • Carter, R., & Mendis, K. N. (2002). Evolutionary and Historical Aspects of the Burden of Malaria. Clinical Microbiology Reviews, 15(4), 564–594. doi:10.1128/CMR.15.4.564-594.2002
I’ve also spent quite a bit of time this autumn reading the pre-print editions of the contributions to Pandemic Disease in the Medieval World: Rethinking the Black Death edited by Monica Green in the inaugural edition of The Medieval Globe, which I’m honored to be a contributor to. Watch this space for more news on this special issue very soon.

Microbial Forensics of a Natural Pneumonic Plague Outbreak

For bioterrorism agents like Yersinia pestis it is necessary to identify the strain and its source specifically enough for forensic use. Categorizing an epidemic isolate and tracing its source is always important for public health measures, but the level of precision is far higher for legal uses. Developing forensic techniques to characterize and parse very similar strains of a species and trace it to a specific location robs terrorists (and states) of the ability to deny responsibility for an attack (Koblentz & Tucker, 2010). The ability to launch a secret and deniable attack on an enemy has been viewed as one of attractive advantages of biological warfare.

A Chinese group led by Ruifu Yang and Yujun Cui recognized that only whole genome sequencing could adequately parse the strains of the monomorphic species Yersinia pestis but that the computing power necessary to compare entire genomic sequences as the database enlarges is impractical (Yan et al, 2014). Unlike most pathogens, typing only specific regions of the genome are just not enough to get a unique genetic fingerprint for low genetic variability pathogens like Yersinia pestis. This is yet another indication of the genomic similarity of all Yersinia pestis strains.

The Chinese group developed a two stage method of classification detailed enough for forensic work.  They took a twelve person outbreak of pneumonic plague contracted from a dog in 2009 in the Qinghai area of Tibet / western China, specifically at Xinghai as their test case (Wang et al, 2010). In the first step they took six cases including the two dogs who died in the outbreak and compared them to 24 strains representing the 23 phylogroups of the phylogenetic tree. This comparison selected which branch of the phylogenetic tree the outbreak belonged. There were no SNP (single nucleotide polymorphisms) different between the seven isolates confirming a common source, one of the dogs based on outbreak narratives. The seven isolates were all the same strain belonging to branch 1.IN2 of the tree. The second step was to then compare the isolates to all known strains of 1.IN2 shown below. Since these strains all come from the Qinghai-Tibetan plateau, they were able to add other strains historically isolated from this region.

Distribution of 1.IN in Qinghai  (site source)
Distribution of 1.IN2 in Qinghai (Yan et al, 2014, click to enlarge)

The results localized the new isolates (r) as being from the same focus as strains g, r, s, t. u plus, interestingly, the 0.PE7 strain (green b) that is over 300 SNPs different from the 1.IN2 strains. All of these other strains from this branch are scattered around the Qinghai region near Lake Qinghai. The polysomy (branch point) that produced all of the 1.IN2 in Xinghai (g,r,s,t,u) is located closer to the eastern end of Lake Qinghai, where the Chinese team hypothesizes this these strains began. The new outbreak isolates did not match any previous isolates from Xinghai which is testimony to the degree of movement of these strains around the region. Without the case narrative, they would not have been able to identify the specific foci at Xinghai, but would have got it to the region of east Qinghai lake. This illustrates how important sampling all of these foci are because a biological attack is likely to be far from its site of environmental isolation. Characterization of all laboratory strains, obviously, needs to happen as well for forensic tracing.

Reconstructing the historical epidemiology of this region will be an area of continuing research. The location of 0.PE7, the most genetically ancestral strain ever found — the closest the common ancestor of all Yersinia pestis, plus the likelihood that the ‘big bang’ epidemic (or epizootic), that produced the third pandemic, represented by node 12, was also in this region. (Each of the nodes represents a bang of evolutionary diversity, with all major branch points in the lineage probably representing large epidemics or epizootics.) The full diversity of strains in this region (unrelated to the outbreak isolates) are not shown in the figure above. This same group lead by Ruifu Yang  produced the primary phylogenetic tree of Yersinia pestis in China that noted that the molecular clock is not constant (Cui et al, 2012), here calculates that N12 is about 212 years old (95% confidence being 116 to 336 years ago) (Yan et al, 2014).  They note that in the history of Qinghai, there was a major human outbreak in the year 1754 CE linked to a Buddhist missionary working in Qinghai and Gansu provinces (Yan et al, 2014). Its is unclear if we can trust this narrative at all; scapegoats are common in plague narratives. Linking the 1.IN2 strains from Qinghai to four of the five o.IN2 isolates from Tibet suggest that the epidemic moved from Qinghai to Tibet in one ancient epidemic, though remaining isolate from Tibet looks like a more recent transmission from Qinghai. Regardless of the movements of 1.IN2, this area is believed to have been a site of long-term survival of Yersinia pestis, potentially over a thousand years, so that it has a lot to teach us about enduring foci.

Microbial forensics has already been used in criminal investigations, court cases and intelligence operations, such as the ‘Amerithrax’ (anthrax) attacks of 2001, anthrax spores sprayed over Japan by a cult, and suspicious plague cases in New York City (Yan et al, 2014). Phylogenetic microbial forensics was successfully used to show the intentional transmission of HIV from Dr Richard Schmidt to his girlfriend in his 1998 trial. This was the first successful use of microbial forensics in a court case (Koblentz & Tucker, 2010). In these cases, isolates are taken from the accused, the victim, other sexual partners, and the local population so show phylogenetic linkage between the accused and victim in the context of the local epidemiology.  The United States, United Kingdom, Sweden, the Netherlands, Japan, Canada, Germany, Australia, Singapore, and now China are involved in the development of microbial forensics (Koblentz & Tucker, 2010; Yan et al, 2014).


Koblentz, G. D., & Tucker, J. B. (2010). Tracing an Attack: The Promise and Pitfalls of Microbial Forensics. Survival, 52(1), 159–186. doi:10.1080/00396331003612521

Yan Y, Wang H, Li D, Yang X, Wang Z, et al. (2014) Two-Step Source Tracing Strategy of Yersinia pestis and Its Historical Epidemiology in a Specific Region. PLoS ONE 9(1): e85374. doi:10.1371/journal.pone.0085374

Wang, H., Cui, Y., Wang, Z., Wang, X., Guo, Z., Yan, Y., et al. (2010). A Dog-Associated Primary Pneumonic Plague in Qinghai Province, China. Clinical Infectious Diseases, 52(2), 185–190. doi:10.1093/cid/ciq107

Cui, Y., Yu, C., Yan, Y., Li, D., Li, Y., Jombart, T., et al. (2012). Historical variations in mutation rate in an epidemic pathogen, Yersinia pestis. Proceedings of the National Academy of Sciences, 110(2), 577–582. doi:10.1073/pnas.1205750110/-/DCSupplemental/sd01.xls